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Sigma-1 Receptor (S1R) Interaction with Cholesterol: Mechanisms of S1R Activation and Its Role in Neurodegenerative Diseases

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Sigma-1 Receptor (S1R) Interaction with Cholesterol: Mechanisms of S1R Activation and Its Role in Neurodegenerative Diseases International Journal of Molecular Sciences Communication Sigma-1 Receptor (S1R) Interaction with Cholesterol: Mechanisms of S1R Activation and Its Role in Neurodegenerative Diseases Vladimir Zhemkov 1, Michal Geva 2, Michael R. Hayden 2,3 and Ilya Bezprozvanny 1,4,* 1 Department of Physiology, UT Southwestern Medical Center, Dallas, TX 75390, USA; [email protected] 2 Prilenia Therapeutics Development LTD, Herzliya 4673304, Israel; [email protected] (M.G.); [email protected] (M.R.H.) 3 Centre for Molecular Medicine and Therapeutics, The University of British Columbia, Vancouver, BC V6H 3V5, Canada 4 Laboratory of Molecular Neurodegeneration, Peter the Great St Petersburg State Polytechnic University, 195251 St. Petersburg, Russia * Correspondence: [email protected] Abstract: The sigma-1 receptor (S1R) is a 223 amino acid-long transmembrane endoplasmic retic- ulum (ER) protein. The S1R modulates the activity of multiple effector proteins, but its signaling functions are poorly understood. S1R is associated with cholesterol, and in our recent studies we demonstrated that S1R association with cholesterol induces the formation of S1R clusters. We propose that these S1R-cholesterol interactions enable the formation of cholesterol-enriched microdomains in the ER membrane. We hypothesize that a number of secreted and signaling proteins are recruited Citation: Zhemkov, V.; Geva, M.; and retained in these microdomains. This hypothesis is consistent with the results of an unbiased Hayden, M.R.; Bezprozvanny, I. Sigma-1 Receptor (S1R) Interaction screen for S1R-interacting partners, which we performed using the engineered ascorbate peroxi- with Cholesterol: Mechanisms of S1R dase 2 (APEX2) technology. We further propose that S1R agonists enable the disassembly of these Activation and Its Role in cholesterol-enriched microdomains and the release of accumulated proteins such as ion channels, Neurodegenerative Diseases. Int. J. signaling receptors, and trophic factors from the ER. This hypothesis may explain the pleotropic Mol. Sci. 2021, 22, 4082. signaling functions of the S1R, consistent with previously observed effects of S1R agonists in various https://doi.org/10.3390/ experimental systems. ijms22084082 Keywords: sigma-1 receptor; endoplasmic reticulum; mitochondria; contact sites; cholesterol; neu- Academic Editor: Carmen Abate rodegeneration; Huntington’s disease; Alzheimer’s disease; amyotrophic lateral sclerosis; drug target Received: 25 March 2021 Accepted: 13 April 2021 Published: 15 April 2021 1. Introduction Publisher’s Note: MDPI stays neutral The sigma-1 receptor (S1R) is a 223 amino acid-long transmembrane protein residing with regard to jurisdictional claims in in the endoplasmic reticulum (ER) [1–3]. S1R attracts significant attention as a potential published maps and institutional affil- drug target for treating neurological disorders [2,4–6] and cancers [6]. iations. S1R is expressed at high levels in the CNS and specifically in the cortex, basal ganglia, and motor neurons of the spinal cord and brainstem [7–10]. The S1R is a chaperone protein that is enriched at the ER/mitochondria-associated membrane (MAM), where it plays an important role in the regulation of multiple cellular mechanisms and is key to maintaining neuronal function and health. This is further supported by human genetic studies, showing Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. that complete loss of function (LOF) mutations in the S1R are associated with a juvenile This article is an open access article form of amyotrophic lateral sclerosis/frontotemporal dementia (ALS/FTD), while partial distributed under the terms and LOF mutations cause late onset ALS [11–14]. Thus, there is a gene dosage relationship conditions of the Creative Commons between S1R activity and the age of onset of ALS with the complete loss of S1R associated Attribution (CC BY) license (https:// with the earliest age of onset. Additional LOF mutations in the S1R cause distal hereditary creativecommons.org/licenses/by/ motor neuropathies (dHMN) [15–19]. Furthermore, S1R expression levels are reduced in 4.0/). sporadic ALS [20], Parkinson’s disease (PD), and Alzheimer’s disease (AD) patients [21,22]. Int. J. Mol. Sci. 2021, 22, 4082. https://doi.org/10.3390/ijms22084082 https://www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2021, 22, 4082 2 of 16 In preclinical models, the genetic ablation of S1R in mice exacerbated pathology and phenotypic presentation of several neurological disorders [23–25]. These results suggest that S1R plays an important role in healthy neuronal physiology. The first prototypic S1R agonist, SKF-10047, was identified in animal behavioral assays, which led to the proposed existence of sigma opioid receptors [26]. However, SKF-10047 binding to sigma binding sites was not blocked by naloxone, an opioid receptor antagonist, and displayed a different stereospecificity [27,28]. Subsequent cloning of sigma binding sites confirmed that they share no homology with opioid G protein-coupled receptors (GPCRs), as well as sharing little homology to any other mammalian protein [29,30]. Se- quence analysis revealed homology with the fungi C7–C8 sterol isomerase. While the S1R does not have isomerase activity, it contains two sterol-like binding domains as part of its ligand-binding site [29]. Recent biochemical and structural analysis indicated that the S1R is a single transmembrane domain protein with a short cytoplasmic tail and a large luminal ligand-binding domain [31,32]. It is suggested that the S1R acts as a molecu- lar chaperone, which can stabilize the native conformation of multiple client proteins in stress conditions [1,33,34]. The S1R can be activated with highly selective synthetic ligands with nanomolar affinity [34–36]. The identity of an endogenous ligand is under investiga- tion, with endogenous steroids (pregnenolone, dehydroepiandrosterone sulfate (DHEA), progesterone) being the most likely candidate [37,38], and N,N-dimethyltryptamine [39], sphingolipids [40], and more recently, choline also investigated [41]. Despite its importance in physiology and disease, the biological function of S1R is poorly understood [3]. This protein is involved in many biological processes and sig- naling pathways including maintenance of calcium homeostasis [42–45], protein fold- ing [42], stress-response [1,42,46,47], autophagy [48,49], and the regulation of cellular excitability [50–52]. The S1R modulates the activity of ion channels via protein–protein interaction [52,53]. The S1R mode of action is not coupled to any known signaling cascade and is more consistent with its role as a modulatory or adaptor protein, or, using a term first coined by Hayashi and Su, a “molecular chaperone” [34,42,54]. Several S1R-interacting partners have been identified and multiple recent reviews comprehensively summarized these S1R interactors and the S1R-induced modulation of their activities [2,3]. Apart from that, S1R is known to interact and mediate the clustering of cholesterol and ceramides in the ER, as shown in cell-based assays [55–58]. We recently demonstrated that S1R is associated with cholesterol-enriched clusters in the membranes using in vitro reconstitution approach [59]. In this review we propose a hypothesis that the biological functions of the S1R are mediated by its ability to form ER signaling cholesterol-enriched lipid microdomains, analogous to the lipid rafts in the plasma membrane [60]. 2. Intracellular Localization of the S1R S1R primarily resides in the ER membrane where it forms microdomains [42,59,61,62]. Its localization is in contrast to the uniform distribution pattern of ER markers, such as the Sec61b protein. A significant proportion of S1R is localized to MAMs, an ER sub-compartment closely associated with the mitochondria [42,59], in proximity to lipid droplets [63], and at the ER-plasma membrane (PM) junctions [59,64]. It is likely that S1R are localized to additional inter-organelle contact sites, but this has not been systematically investigated. MAMs are distinct from the rest of the ER as they contain enzymes involved in lipid synthesis, calcium signaling, cholesterol metabolism, and the ER stress-response pathways [65–69]. A detailed protein composition of MAMs was initially characterized by biochemical purifications [70,71] and more recently established using sophisticated proximity labeling approaches [72–74]. While the precise lipid composition of the MAMs has not yet been elucidated, recent evidence suggests that cholesterol and ceramide content is significantly higher in MAMs compared to the rest of the ER [57,75,76]. Therefore, MAMs can be thought of as specialized Int. J. Mol. Sci. 2021, 22, 4082 3 of 16 ER signaling domains characterized by unique protein and lipid compositions, similar to PM lipid rafts [60]. While PM lipid and protein heterogeneity was visualized using the giant plasma membrane-derived vesicle technique [77–79], only recently was a similar method to yield endomembrane-derived giant unilamellar vesicle (GUV)-like vesicles developed [80]. Using this approach, it was observed that certain, but not all ER contact sites (such as ER-mitochondria, ER-PM, and ER-lipid droplets) showed separation of the glyco- sylphosphatidylinositol (GPI) ER-targeted marker with a strong affinity for lipid-ordered phase [80]. Similar lipid and protein compartmentalization were recently observed at the inter-organelle contact sites in yeast [81], providing additional experimental
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